A Novel SLC9A6 Mutation Associated with Christianson Syndrome in a Non-Consanguineous Iranian Family: A Case Report

CASE REPORT
Mehdi Hashemipour, Mostafa Neissi, Mahsa Rashid, Karim Sevari, Motahareh Sheikh-Hosseini, Adnan Issa Al-Badran

 
For citation: Hashemipour M, Neissi M, Rashid M, Sevari K, Sheikh-Hosseini M, Al-Badran AI. A Novel SLC9A6 Mutation Associated with Christianson Syndrome in a Non-Consanguineous Iranian Family: A Case Report. International Journal of Biomedicine. 2024;14(3):536-540. doi:10.21103/Article14(3)_CR4
 
Originally published September 6, 2024

Abstract: 

Introduction: Christianson syndrome is a neurological disorder characterized by recurrent seizures resulting from abnormal brain neuron discharge. Primarily emerging in childhood, Christianson syndrome is marked by a complex clinical presentation intertwined with social and learning disabilities. Moreover, it is often associated with severe epilepsy, encompassing various debilitating neurological conditions marked by frequent seizures and developmental challenges.
Case Presentation: A 2-year-old Iranian boy presented with developmental delays and tonic-clonic seizures. Physical examination revealed microcephaly, motor delays, and other neurological abnormalities. Genetic testing identified a novel hemizygous missense mutation, c.577G>A; p.Gly193Arg, in the SLC9A6 gene. This mutation likely contributes to Christianson syndrome, characterized by intellectual disability, epilepsy, and other neurological impairments. Further validation confirmed the mutation's presence, highlighting its significance in the patient's clinical presentation.
Conclusion: The c.577G>A; p.Gly193Arg mutation in the SLC9A6 gene sheds light on the pathogenesis of Christianson syndrome by disrupting the normal function of the SLC9A6 protein crucial for neuronal development. This discovery underscores the significance of SLC9A6 in maintaining cellular homeostasis and highlights its role in neurological disorders. Further exploration of this mutation's effects may lead to targeted therapeutic strategies for managing the debilitating symptoms of Christianson syndrome.

Keywords: 
Christianson syndrome • SLC9A6 gene • mutation
References: 
  1. Liu J, Tong L, Song S, Niu Y, Li J, Wu X, et al. Correction to: Novel and de novo mutations in pediatric refractory epilepsy. Mol Brain. 2018 Oct 16;11(1):59. doi: 10.1186/s13041-018-0399-y. Erratum for: Mol Brain. 2018 Sep 5;11(1):48. PMID: 30326925; PMCID: PMC6192341.
  2. McTague A, Howell KB, Cross JH, Kurian MA, Scheffer IE. The genetic landscape of the epileptic encephalopathies of infancy and childhood. Lancet Neurol. 2016 Mar;15(3):304-16. doi: 10.1016/S1474-4422(15)00250-1. Epub 2015 Nov 17. PMID: 26597089.
  3. Wirrell E. Infantile, Childhood, and Adolescent Epilepsies. Continuum (Minneap Minn). 2016 Feb;22(1 Epilepsy):60-93. doi: 10.1212/CON.0000000000000269. PMID: 26844731.
  4. Deane EC, Ilie AE, Sizdahkhani S, Das Gupta M, Orlowski J, McKinney RA. Enhanced recruitment of endosomal Na+/H+ exchanger NHE6 into Dendritic spines of hippocampal pyramidal neurons during NMDA receptor-dependent long-term potentiation. J Neurosci. 2013 Jan 9;33(2):595-610. doi: 10.1523/JNEUROSCI.2583-12.2013. PMID: 23303939; PMCID: PMC6704919.
  5. Mignot C, Héron D, Bursztyn J, Momtchilova M, Mayer M, Whalen S, et al. Novel mutation in SLC9A6 gene in a patient with Christianson syndrome and retinitis pigmentosum. Brain Dev. 2013 Feb;35(2):172-6. doi: 10.1016/j.braindev.2012.03.010. Epub 2012 Apr 26. PMID: 22541666.
  6. Ikeda A, Yamamoto A, Ichikawa K, Tsuyusaki Y, Tsuji M, Iai M, et al. Epilepsy in Christianson syndrome: Two cases of Lennox-Gastaut syndrome and a review of literature. Epilepsy Behav Rep. 2019 Dec 5;13:100349. doi: 10.1016/j.ebr.2019.100349. PMID: 31879735; PMCID: PMC6920258.
  7. Cardon M, Evankovich KD, Holder JL Jr. Exonic deletion of SLC9A9 in autism with epilepsy. Neurol Genet. 2016 Feb 25;2(2):e62. doi: 10.1212/NXG.0000000000000062. PMID: 27123481; PMCID: PMC4830193.
  8. Padmanabha H, Saini AG, Sahu JK, Singhi P. Syndrome of X linked intellectual disability, epilepsy, progressive brain atrophy and large head associated with SLC9A6 mutation. BMJ Case Rep. 2017 Dec 22;2017:bcr2017222050. doi: 10.1136/bcr-2017-222050. PMID: 29275387; PMCID: PMC5780601.
  9. Neissi M, Mabudi H, Mohammadi-Asl J. AHI1 gene mutation in a consanguineous Iranian family affected by Joubert syndrome: A case report. Clin Case Rep. 2021 Oct 23;9(10):e05002. doi: 10.1002/ccr3.5002. PMID: 34721863; PMCID: PMC8538011.
  10. Neissi M, Al-Badran AI, Mohammadi-Asl J. A Novel Deleterious MYO15A Gene Mutation Causes Nonsyndromic Hearing Loss. Iran J Otorhinolaryngol. 2024 Jan;36(1):355-360. doi: 10.22038/IJORL.2023.69889.3372. PMID: 38259694; PMCID: PMC10800138.
  11. Neissi M, Sheikh-Hosseini M, Mohammadi-Asl J. Retinitis pigmentosa-1 due to an RP1 mutation in a consanguineous Iranian family: Report of a novel mutation. Clin Case Rep. 2024 Mar 14;12(3):e8666. doi: 10.1002/ccr3.8666. PMID: 38487646; PMCID: PMC10940001.
  12. Neissi M, Mohammadi-Asl M, Roghani M, Al-Badran AI, Mohammadi-Asl J. Mutation Detection in MYO15A Gene in an Iranian Family with Non-Syndromic Hearing Loss. Int J Biomed. 2024;14(1):165-169. doi:10.21103/Article14(1)_CR3.
  13. Petitjean H, Fatima T, Mouchbahani-Constance S, Davidova A, Ferland CE, Orlowski J, et al. Loss of SLC9A6/NHE6 impairs nociception in a mouse model of Christianson syndrome. Pain. 2020 Nov;161(11):2619-2628. doi: 10.1097/j.pain.0000000000001961. PMID: 32569089; PMCID: PMC7566297.
  14. Shepherd JD, Huganir RL. The cell biology of synaptic plasticity: AMPA receptor trafficking. Annu Rev Cell Dev Biol. 2007;23:613-43. doi: 10.1146/annurev.cellbio.23.090506.123516. PMID: 17506699.
  15. Barford K, Deppmann C, Winckler B. The neurotrophin receptor signaling endosome: Where trafficking meets signaling. Dev Neurobiol. 2017 Apr;77(4):405-418. doi: 10.1002/dneu.22427. Epub 2017 Feb 24. PMID: 27503831; PMCID: PMC5661883.
  16. Fuster DG, Alexander RT. Traditional and emerging roles for the SLC9 Na+/H+ exchangers. Pflugers Arch. 2014 Jan;466(1):61-76. doi: 10.1007/s00424-013-1408-8. Epub 2013 Dec 12. PMID: 24337822.
  17. Avila J, Lucas JJ, Perez M, Hernandez F. Role of tau protein in both physiological and pathological conditions. Physiol Rev. 2004 Apr;84(2):361-84. doi: 10.1152/physrev.00024.2003. PMID: 15044677.
  18. Lee G, Neve RL, Kosik KS. The microtubule binding domain of tau protein. Neuron. 1989 Jun;2(6):1615-24. doi: 10.1016/0896-6273(89)90050-0. PMID: 2516729.
  19. Garbern JY, Neumann M, Trojanowski JQ, Lee VM, Feldman G, Norris JW, et al. A mutation affecting the sodium/proton exchanger, SLC9A6, causes mental retardation with tau deposition. Brain. 2010 May;133(Pt 5):1391-402. doi: 10.1093/brain/awq071. Epub 2010 Apr 15. PMID: 20395263; PMCID: PMC2859154.
  20. Pescosolido MF, Kavanaugh BC, Pochet N, Schmidt M, Jerskey BA, Rogg JM, et al. Complex Neurological Phenotype in Female Carriers of NHE6 Mutations. Mol Neuropsychiatry. 2019 Apr;5(2):98-108. doi: 10.1159/000496341. Epub 2019 Mar 6. PMID: 31192222; PMCID: PMC6528080.
  21. Buée L, Bussière T, Buée-Scherrer V, Delacourte A, Hof PR. Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Brain Res Rev. 2000 Aug;33(1):95-130. doi: 10.1016/s0165-0173(00)00019-9. PMID: 10967355.

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Received June 29, 2024.
Accepted August 28, 2024.
©2024 International Medical Research and Development Corporation.